THE DISPOSITION OF PYRIMETHAMINE IN THE ISOLATED PERFUSED RAT-LIVER

The disposition of pyrimethamine [antimalaria-drug] base in the isolated perfused rat liver (IPRL) preparation, after the administration of pyrimethamine (0.5 mg, 5 .mu.Ci), was investigated. In the 0.5 half h of the study, pyrimethamine underwent marked hepatic uptake; thereafter, perfusate plasma drug levels declined monoexponentially, with a half life (t1/2) of 3.0 .+-. 1.0 h. Area under the perfusate plasma concentration/time curve (AUC)0.fwdarw..infin. was 6.9 .+-. 1.9 .mu.g/h per ml. Pyrimethamine was found to be a low clearance compound (78.4 .+-. 25.3 ml/h = 8.6% of liver perfusate flow) with a large volume of distribution (267.5 .+-. 55.3 ml) in the IPRL. The combined AUC(0.fwdarw.5h)for pyrimethamine (AUC 4.8 .+-. 0.5 .mu.g h per ml) and pyrimethamine 3-N-oxide (AUC0.fwdarw.5h 0.9 .+-. 0.6 .mu.g/h per ml) accounted for 57% of the total AUC0.fwdarw.5h of [14C]radioactivity (10.0 .+-. 2.6 .mu.g/h per ml). This indicates the presence of metabolites of pyrimethamine as yet unidentified in the perfusate. Biliary excretion of [14C]during the course of the IPRL preparations was extensive (29.0 .+-. 10.3%), though only a small proportion was due to pyrimethamine and the 3-N-oxide metabolite. The majority of radioactivity in the bile was attributable to highly polar, but unidentified, metabolites of pyrimethamine. At the conclusion of each experiment (5 h), a significant proportion of [14C] radioactivity was recovered from the livers (22.9 .+-. 5.3%). Subsequent HPLC [high performance liquid chromatography] analysis of the liver tissue indicated this to be unchanged pyrimethamine, with trace levels of the 3-N-oxide metabolite. Sub-cellular fractionation of the homogenized livers revealed the most pronounced localization of pyrimethamine to be in the lipid rich 10,000 g pellet (13.0 .+-. 2.6%), the remainder being distributed equally between the 105,000 g pellet and supernatant. Neither pyrimethamine, [14C] radioactivity, nor pyrimethamine 3-N-oxide were extensively taken up by red cells throughout the study. The large volume of distribution (267.5 .+-. 55.3 ml) underlines the extent of pyrimethamine localization in the liver.